Glutamine addiction and therapeutic strategies in pancreatic cancer

Abstract

Pancreatic cancer remains one of the most lethal diseases worldwide owing to its late diagnosis, early metastasis, and poor prognosis. Because current therapeutic options are limited, there is an urgent need to investigate novel targeted treatment strategies. Pancreatic cancer faces significant metabolic challenges, principally hypoxia and nutrient deprivation, due to specific microenvironmental constraints, including an extensive desmoplastic stromal reaction. Pancreatic cancer cells have been shown to rewire their metabolism and energy production networks to support rapid survival and proliferation. Increased glucose uptake and glycolytic pathway activity during this process have been extensively described. However, growing evidence suggests that pancreatic cancer cells are glutamine addicted. As a nitrogen source, glutamine directly (or indirectly via glutamate conversion) contributes to many anabolic processes in pancreatic cancer, including amino acids, nucleobases, and hexosamine biosynthesis. It also plays an important role in redox homeostasis, and when converted to α-ketoglutarate, glutamine serves as an energy and anaplerotic carbon source, replenishing the tricarboxylic acid cycle intermediates. The present study aims to provide a comprehensive overview of glutamine metabolic reprogramming in pancreatic cancer, focusing on potential therapeutic approaches targeting glutamine metabolism in pancreatic cancer.

Keywords: Cancer treatment; Glutamine metabolism; Pancreatic cancer; Therapeutic strategies.

Figure 1

Metabolism of glutamine in pancreatic cancer. Glutamine enters the cells through four receptors (SLC1, SLC6, SLC7, and SLC38) and can be incorporated into various metabolic pathways either as a nitrogen source or as a carbon source, which is important for the synthesis of nucleotides, non-essential amino acids, glucosamine and gluconeogenesis, the tricarboxylic acid (TCA) cycle, and glutathione metabolism. Under normal physiological conditions, glutamine can be converted to α-ketoglutarate by canonical pathway to replenish the TCA cycle metabolites, which is differ from the non-canonical pathway of glutamine using in pancreatic cancer. TCA: Tricarboxylic acid; αKG: α-ketoglutarate; GOT1: Aspartate transaminase; OAA: Oxaloacetate; GLUD1: Glutamate dehydrogenase; NEAAs: Non-essential amino acids.

Figure 2

Glutamine metabolic reprogramming. Glutamine is a key nutrient in tumourgenesis and Glutamine metabolic reprogramming in pancreatic cancer help enhance metabolic use of glutamine in cancer cells. Pancreatic cancer cells affect glutamate metabolism through Myc, Kras mutations, regulated in DNA damage and development 1, p53, Protein arginine methyltransferase 4, Ras transform, β-catenin/TCF 7 complex. REDD1: Regulated in DNA damage and development 1; ROS: Reactive oxygen species; GLS: Glutaminase; mTOR: the mammalian target of rapamycin; MDH1: Malate dehydrogenase 1; GSH: Glutathione.

Figure 3

Targeting glutamine metabolism in pancreatic cancer. A few compounds that target glutamine metabolism by inhibiting glutaminase 1, Ivosidenib (AG-120) or aspartate transaminase (GOT1), blocking activity of alanine-serine-cysteine transporter 2 (ASCT2), ASCT2 knockdown, affecting Kas/c-Myc are studied for the treatment of pancreatic cancer. ROS: Reactive oxygen species; GLS: Glutaminase; BPTES: Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl) ethyl sulfide; AO: Aspulvinone O; mTOR: Mammalian target of rapamycin; IDH1: Isocitrate dehydrogenase.